This invention relates to methods for treatment or prevention of precancerous lesions.
Each year in the United States alone, untold numbers of people develop precancerous lesions. These lesions exhibit a strong tendency to develop into malignant tumors, or cancer. Such lesions include lesions of the breast (that can develop into breast cancer), lesions of the skin (that can develop into malignant melanoma or basal cell carcinoma), colonic adenomatous polyps (that can develop into colon cancer), and other such neoplasms. Compounds which prevent or induce the remission of existing precancerous or cancerous lesions or carcinomas would greatly reduce illness and death from cancer.
Approximately 60,000 people die from colon cancer, and over 150,000 new cases of colon cancer are diagnosed each year. For the American population as a whole, individuals have a six percent lifetime risk of developing colon cancer, making it the second most prevalent form of cancer in the country. Colon cancer is also prevalent in Western Europe. It is believed that increased dietary fat consumption is increasing the risk of colon cancer in Japan.
In addition, the incidence of colon cancer reportedly increases with age, particularly after the age of 40. Since the mean ages of populations in America and Western Europe are increasing, the prevalence of colorectal cancer should increase in the future.
To date, little progress has been made in the prevention and treatment of colorectal cancer, as reflected by the lack of change in the five-year survival rate over the last few decades. The only cure for this cancer is surgery at an extremely early stage. Unfortunately, most of these cancers are discovered too late for surgical cure. In many cases, the patient does not experience symptoms until the cancer has progressed to a malignant stage.
In view of these grim statistics, efforts in recent years have concentrated on colon cancer prevention. Colon cancer usually arises from pre-existing benign neoplastic growths known as polyps. Prevention efforts have emphasized the identification and removal of colonic polyps. Polyps are identified by x-ray and/or colonoscopy, and usually removed by devices associated with the colonoscope. The increased use of colon x-rays and colonoscopies in recent years has detected clinically significant precancerous polyps in four to six times the number of individuals per year that acquire colon cancer. During the past five years alone, an estimated 3.5 to 5.5 million people in the United States have been diagnosed with adenomatous colonic polyps, and it is estimated that many more people have or are susceptible to developing this condition, but are as yet undiagnosed. In fact, there are estimates that 10-12 percent of people over the age of 40 will form clinically significant adenomatous polyps.
Removal of polyps has been accomplished either with surgery or fiber-optic endoscopic polypectomyxe2x80x94procedures that are uncomfortable, costly (the cost of a single polypectomy ranges between $1,000 and $1,500 for endoscopic treatment and more for surgery), and involve a small but significant risk of colon perforation. Overall, about $2.5 billion is spent annually in the United States in colon cancer treatment and prevention.
As indicated above, each polyp carries with it a chance that it will develop into a cancer. The likelihood of cancer is diminished if a polyp is removed. However, many of these patients demonstrate a propensity for developing additional polyps in the future. They must, therefore, be monitored periodically for the rest of their lives for polyp reoccurrence.
In most cases (i.e. the cases of so-called common sporadic polyps), polyp removal will be effective to reduce the risk of cancer. In a small percentage of cases (i.e. the cases of the so-called polyposis syndromes), removal of all or part of the colon is indicated. The difference between common sporadic polyps and polyposis syndromes is dramatic. Common sporadic polyp cases are characterized by relatively few polyps, each of which can usually be removed leaving the colon intact. By contrast, polyposis syndrome cases can be characterized by many (e.g. hundreds or more) of polypsxe2x80x94literally covering the colon in some casesxe2x80x94making safe removal of the polyps impossible short of surgical removal of the colon.
Because each polyp carriers with it the palpable risk of cancerous development, polyposis syndrome patients invariably develop cancer if left untreated. Surgical removal of the colon is the conventional treatment. Many of these patients have undergone a severe change in lifestyle as a result of the disfiguring surgery. Patients have strict dietary restrictions, and many must wear ostomy appliances to collect their intestinal wastes.
The search for drugs useful for treating and preventing cancer is intensive. Indeed, much of the focus of cancer research today is on the prevention of cancer because therapy is often not effective and has severe side effects. Cancer prevention is important for recovered cancer patients who retain a risk of cancer reoccurrence. Also, cancer prevention is important for people who have not yet had cancer, but have hereditary factors that place them at risk of developing cancer. With the development of new diagnostic screening technologies, it is possible to identify those with high risk factors, such as the potential for polyposis syndrome, who would greatly benefit from chemopreventive drugs. Therefore, finding such anti-cancer drugs that can be used for prolonged preventive use is of vital interest to many people.
One way to find such drugs is to screen thousands of compounds for the same biological activity found in known chemopreventive and chemotherapeutic drugs. Most such drugs are now believed to kill cancer cells by inducing apoptosis, or as sometimes referred to as xe2x80x9cprogrammed cell death.xe2x80x9d Apoptosis naturally occurs in virtually all tissues of the body, and especially in self-renewing tissues such as bone marrow, gut, and skin. Apoptosis plays a critical role in tissue homeostasis, that is, it ensures that the number of new cells produced are correspondingly offset by an equal number of cells that die. For example, the cells in the intestinal lining divide so rapidly that the body must eliminate cells after only three days in order to prevent the overgrowth of the intestinal lining.
Recently, scientists have realized that abnormalities of apoptosis can lead to the formation of precancerous lesions and carcinomas. Also, recent research indicates that defects in apoptosis plays a major role in other diseases in addition to cancer. Consequently, compounds that modulate apoptosis could be used to prevent or control cancer, as well as used in the treatment of other diseases.
Unfortunately, even though known chemotherapeutic drugs may exhibit such desirable apoptosis effects, most chemotherapeutic drugs have serious side effects that prohibit their long term use, or use in otherwise healthy individuals with precancerous lesions. These side effects, which are a result of the high levels of cytotoxicity of the drugs, include hair loss, weight loss, vomiting and bone marrow immune suppression. Therefore, there is a need to identify new drug candidates for therapy that do not have such serious side effects in humans.
This invention is a method of treating patients with precancerous lesions or neoplasms by administering a pharmacologically effective amount of a compound of Formula I below to a patient in need of such treatment. Such compositions are effective in modulating apoptosis, and eliminating and inhibiting precancerous lesions, and neoplastic cells.
As discussed above, this invention is a method of treating a patient with precancerous lesions or neoplasms by administering a pharmacologically effective amount of the phenyl cycloamino pyrimidinone derivative represented by the following formula (I), or the pharmacologically acceptable salt thereof; 
wherein R1, R2 and R3 may be located at any of the available positions on the phenyl ring, each of R1, R2 and R3 may be independently selected from hydrogen, halogen, a lower alkyl group, such as having 1 to 6 carbon atoms, a lower alkoxy, a lower alkenyl, a lower alkenoxy, a lower alkyl thio, a lower alkylamino, a di(lower)alkylamino, a cyano, an acylamino, a carboxyl, a carboalkoxy, a lower alkoxycarbonyl, a lower alkylcarbonyl a cyclo(lower)alkoxy and cyclo(lower)alkyl (lower)alkoxy in which the ring contains 3 to 8 carbon atoms, preferably 3-6 carbon atoms, a phenyl(lower) alkoxy a nitrogen containing ring, a lower alkylcarbamoyloxy, or a halogen substituted lower alkoxy group.
Further, R3 may be xe2x80x94SOxe2x80x94NHR12R13, NO2, NH2, NHCOR14, NHSO2R14 or N(SO2R14)2; wherein R12 and R13 are each independently selected from H and C1-C4 alkyl optionally substituted with CO2R5, OH, pyridyl, 5-isoxazolin-3-onyl, morpholino or 1-imidazolidin-2-onyl; or together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino, morpholino, 1-pyrazolyl or 4-(NR15)-1-piperazinyl group wherein any of said groups may optionally be substituted with one or two substitutents selected from C1-C4 alkyl, CO2R9, NH2 and OH; R14 is C1-C4 alkyl or pyridyl; and R15 is H, C1-C4 alkyl or (hydroxy)C2-C3 alkyl.
Preferably, R1, R2 and R3 are independently a hydrogen, a halogen, a lower alkyl, a lower alkenyl, a lower alkoxy, a lower alkenyloxy, a phenyl(lower) alkoxy, a cyclo(lower)alkoxy. Preferably, R3 is substituted at position 2 on the phenyl ring, in which case it is preferred that R1 and R2 are hydrogen. More preferably R3 is lower alkoxy, lower alkenoxy, cyclopropylmethoxy or benzoxy. Most preferably R3 is n-propyloxy.
R4 may be a hydrogen, lower alkyl, a lower alkoxy, a phenyl, a hydroxy, a halogen, xe2x80x94NHCOR5, xe2x80x94NHCONHR6, 5-tetrazolyl, xe2x80x94CO2R7, a cyano, xe2x80x94CONR8R9, or xe2x80x94NR10R11, wherein R5 to R9 are independently hydrogen or lower alkyl or R9 may be 5-tetrazolyl, and R10 and R11 are independently hydrogen or lower alkyl optionally substituted by hydroxy provided that the carbon atom adjacent to the nitrogen atom is not substituted by hydroxy.
Further, R4 is C1-6 alkylthio, C1-6alkyl-sulphonyl, hydrazino, or xe2x80x94NR10R11, wherein R10 and R11 together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino, hexahydroazepino, morpholino or piperazino ring, on R10 and R11 C3-5cycloalkyl or C1-6alkyl which is optionally substituted by xe2x80x94CF3, phenyl, xe2x80x94S(O)nC1-6alkyl wherein n is 0, 1 or 2, xe2x80x94OR6, xe2x80x94CO2R7 or xe2x80x94NR8R9 wherein R6 to R9 are independently hydrogen or C1-6alkyl, provided that the carbon atom adjacent to the nitrogen atom is not substituted by said xe2x80x94S(O)nC1-6alkyl, xe2x80x94OR6 or xe2x80x94NR8R9 groups.
Preferably, R4 is a phenyl, a lower alkyl, a hydroxy, a lower alkoxy or xe2x80x94CONR8R9. Preferably, when R4 is positioned on the pyrimidinone ring adjacent the oxygen, R4 is xe2x80x94CONR8R9, in which case, it is preferred that R8 is hydrogen and R9 is 5-1H-tetrazolyl.
X1, X2, X3 and X4 may be independently nitrogen or carbon with the proviso that: at least one of X1, X2, X3 and X4 must be nitrogen and at least one of X1, X2, X3 and X4 must be carbon; any two of X1, X2, X3 and X4 may be nitrogen; when X2 and X4 are nitrogen, X3 must be carbon; and, when X1 and X3 are nitrogen, X2 must be carbon.
A preferred group of compounds of formula (I) is that wherein R4 is H, n-propyl, CN or CONH2; R1 is ethoxy; R2 is hydrogen; R3 is SO2NR12R13, NO2, NH2, NHCOCH(CH3)2, NHSO2CH(CH3)2, NHSO2(3-pyridyl)]2; R12 is H, methyl or 2-hydroxyethyl; R13 is methyl optionally substituted with 2-pyridyl or 5-isoxazolin-3-onyl, or ethyl 2-substituted with OH, CO2CH2CH3, morpholino or 1-imidazolidin-2-onyl, or R12 and R13 together with the nitrogen atom to which they are attached form a (4- CO2R5)piperidino, 5-amino-3-hydroxy-1-pyrazolyl or 4-(NR15)-1-piperazinyl group; R5 is H or ethyl; R15 is H, methyl or 2-hydroxyethyl; and X1 is nitrogen. More preferably, R1 is at position 2 and R3 is at position 5 on the phenyl ring.
A particularly preferred group of compounds of formula (I) is that wherein R4 is n-propyl or CN; R1 is ethoxy; R2 is hydrogen; R3 is SO2NR12R13, NHSO2CH(CH3)2 , NHSO2(3-pyridyl) or N[SO2(3-pyridyl)]2; R12 is H or methyl; R13 is methyl, or ethyl 2-substituted with CO2CH2CH3, morpholino or 1-imidazolidin-2-onyl, or R12 and R13 together with the nitrogen atom to which they are attached form a (4-CO2R3)piperidino or 4-(NR15)-1-piperazinyl group; R5 is H or ethyl; and R15 is H, methyl or 2-hydroxyethyl.
xe2x80x9cAlkyl groupxe2x80x9d refers to straight or branched chain C1-C12 groups such as methyl, ethyl, propyl, iso-propyl, n-butyl, t-butyl and amyl. xe2x80x9cAlkoxy groupxe2x80x9d refers to hydroxy-substituted alkyl groups such as methoxy, ethoxy, propoxy, butoxy and amyloxy. xe2x80x9cAlkoxycarbonyl groupxe2x80x9d refers to carbonyl-substituted alkoxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, amyloxycarbonyl, etc. xe2x80x9cAlkylcarbonyl groupxe2x80x9d refers to carbonyl-substituted alkyl groups such as acetyl, propionyl, butyryl or others. xe2x80x9cHalogenxe2x80x9d refers to fluorine, chlorine, bromine and iodine. xe2x80x9cLowerxe2x80x9d refers to 6 or less carbon atoms.
The pharmacologically acceptable salt includes inorganic acid salts such as hydrochloride, hydrobromide, sulfate and phosphate; organic acid salts such as acetate, maleate, tartrate, methanesulfonate, benzenesulfonate and toluenesulfonate; and amino acid salts such as argininate, aspartate and glutamate. Further, some of the compounds may form metal salts such as Na, K, Ca or Mg, and the pharmacologically acceptable salt of formula (I) also includes these metal salts.
Although the compound of formula I may be present as various isomers including geometrical isomers, i.e., cis-isomer and trans-isomer. and optical isomers, i.e., d-isomer and 1-isomer depending upon the kinds and combination of the substituents, it is needless to say that the compounds include all of the isomers.
As used herein, the term xe2x80x9cprecancerous lesionxe2x80x9d refers to lesions that exhibit histologic changes which are associated with an increased risk of cancer development. Examples include adenomatous polyps of the colon, dysplastic nevi of the skin and atypical hyperplasia of the breasts. Certain syndromes that commonly display precancerous lesions are also referred to by the term xe2x80x9cprecancerousxe2x80x9d including dysplastic nevus syndrome and the colonic polyposis syndromes. xe2x80x9cPrecancerousxe2x80x9d refers to these lesions or syndromes of various tissues whether or not the lesions are clinically identifiable.
As used herein, the term xe2x80x9ccarcinomasxe2x80x9d refers to lesions which are cancerous. Examples include malignant melanomas, breast cancer, and colon cancer.
As used herein, the term, xe2x80x9cneoplasmxe2x80x9d refers to both precancerous and cancerous lesions.
As used herein, the term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d refers to chloro, bromo, fluoro and iodo groups, and the term xe2x80x9calkylxe2x80x9d refers to straight, branched or cyclic alkyl groups.
Compounds of formula I may be formulated into compositions together with pharmaceutically acceptable carriers for injection, oral administration in solid or liquid form, or for rectal administration, although carriers for oral administration are most preferred.
Pharmaceutically acceptable carriers for oral administration include capsules, tablets, pills, powders, troches and granules. In such solid dosage forms, the carrier can comprise at least one inert diluent such as sucrose, lactose or starch. Such carriers can also comprise, as is normal practice, additional substances other than diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, troches and pills, the carriers may also comprise buffering agents. Carriers such as tablets, pills and granules can be prepared with enteric coatings on the surfaces of the tablets, pills or granules. Alternatively, the enterically coated compound can be pressed into a tablet, pill, or granule, and the tablet, pill or granules for administration to the patient. Preferred enteric coatings include those that dissolve or disintegrate at colonic pH such as shellac or Eudraget S.
Pharmaceutically acceptable carriers include liquid dosage forms for oral administration, e.g. pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.
Pharmaceutically acceptable carriers for rectal administration are preferably suppositories which may contain, in addition to the compounds of Formula I, excipients such as cocoa butter or a suppository wax.
The pharmaceutically acceptable carrier and compounds of Formula I are formulated into unit dosage forms for administration to a patient. The dosage levels of active ingredient (i.e. compounds of Formula I) in the unit dosage may be varied so as to obtain an amount of active ingredient effective to achieve polyp-eliminating activity in accordance with the desired method of administration (i.e. oral or rectal). The selected dosage level therefore depends upon the nature of the active compound administered, the route of administration, the desired duration of treatment, and other factors. If desired, the unit dosage may be such that the daily requirement for active compound is in one dose, or divided among multiple doses for administration, e.g. two to four times per day.
In another form, the invention is a method of inhibiting the growth of neoplastic cells by exposing them to an effective amount of the compound of formula [I] above.
In still another form, the invention is a method of inducing apoptosis in human cells by exposing those cells to an effective amount of the compound of formula [I] above where such cells are sensitive to this compound.
Additionally, in yet another form, the invention is a method of treating a patient having a disease which would benefit from regulation of apoptosis by treating the patient with an effective amount of the compound of formula [I] above. The regulation of apoptosis is believed to play an important role in diseases associated with abnormalities of cellular growth patterns such as benign prostatic hyperplasia, neurodegenerative diseases such as Parkinson""s disease, autoimmune diseases including multiple sclerosis and rheumatoid arthritis, infectious diseases such as AIDS, and other diseases, as well.
The foregoing may be better understood from the following examples, which are presented for purposes of illustration and are not intended to limit the scope of the invention. As used in the following examples, the references to substituents such as R, R1, R2 etc., refer to the corresponding compounds and substituents in the Formula above.
Preferable specific examples of the compound will now be described in order to facilitate the understanding of the present invention, though it is needless to say that the compounds of the present invention are not limited to these examples.